Haemophilus influenzae is an important pathogen in man. Encapsulated H. influenzae type b is a leading cause of bacteremia, pneumonia and meningitis in infancy in the United States. Unencapsulated or nontypable H. influenzae is an important cause of sepsis in the newborn and in certain immunocompromised patients and of infection in the middle ear and in the respiratory tract in adults and children. The goal of this proposed study is to define the molecular bases of the clearance of H. influenzae from the bloodstream. Previous studies indicate that this process of clearance depends upon receptor-mediated phagocytosis of these pathogens by fixed macrophages. Therefore, in the proposed work the interaction of H. influenzae with the macrophage will be examined. Since the understanding of how microbes interact with macrophages is largely based on work done with intracellular pathogens, the proposed study will concentrate on examining the role of specific receptors and ligands previously defined to mediate binding and ingestion of these organisms. This study, however, will begin to define how these mechanisms are used in defending the host from extracellular bacterial pathogens. The approach will be to determine (1) the specificity and physiology of the macrophage receptors which mediate direct binding of H. influenzae, (2) the bacterial surface components which act as ligands to these receptors, (3) the effects of antibody and serum complement as ligands for the interaction of H. influenzae with macrophages and (4) the potential for macrophage activation to modify this bacteria-macrophage interaction. This study will be conducted using in vitro culture systems for both murine and human macrohages along with in vivo study of H. influenzae bloodstream clearance in a murine model. This work is expected to define mechanisms critical in defending the immune and nonimmune host from infection due to H. influenzae. In doing so, it is expected that advances in designing effective prophylactic and therapeutic regimens aimed at these infections will be realized.